The present invention relates to novel 1,2,3,4-tetrahydroisoquinoline derivatives of the general formula 1 and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of the general formula 1 and especially their use as neurohormonal antagonists.
Urotensin II is a cyclic 11-amino acid peptide that has some sequence similarity to, but is not homologous with, somatostatin-14. Urotensin II was first isolated and sequenced from fish spinal cord (Bern H A, Pearson D, Larson B A, Nishioka R S. Neurohormones from fish tails: the caudal neurosecretory system. I. xe2x80x9cUrophysiologyxe2x80x9d and the caudal neurosecretory system of fishes. Recent Prog. Horm. Res. (1985) 41, 533-552), and has since been found in a wide variety of vertebrate and invertebrate species. Human urotensin II is synthesized in a prepro-form from a single gene located at chromosome 1p36.21, and two cDNA splice variants which differ in their putative signal peptide sequence have been isolated from human colon tumor and human placenta (GenBank Accession Nr. O95399). The putative prohormone convertase dibasic cleavage site is strictly conserved across species. The mature 11-amino acid peptide contains a C-terminal disulfide-bridged 6-amino acid loop which is also strictly conserved, while the N-terminal portion of the mature cyclic peptide can vary considerably across species.
Urotensin II exerts potent and complex hemodynamic actions in mammals (Douglas S A, Sulpizio A C, Piercy V, Sarau H M, Ames R S, Alyar N V, Ohlstein E H, Willette R N. xe2x80x9cDifferential vasoconstrictor activity of human urotensin-II in vascular tissue isolated from the rat, mouse, dog, pig, marmoset and cynomolgus monkey.xe2x80x9d Br. J. Pharmacol. (2000) 131, 1262-1274. Douglas, S A, Ashton D J, Sauermelch C F, Coatney R W, Ohlstein D H, Ruffolo M R, Ohlstein E H, Alyar N V, Willette R xe2x80x9cHuman Urotensin-II is a potent vasoactive peptide: pharmacological characterization in the rat, mouse, dog and primate.xe2x80x9d J. Cardiovasc. Pharmacol. (2000) 36, Suppl 1:S163-6). The peptide effectively constricts isolated mammalian arteries. The potency of vasoconstriction is an order of magnitude greater than that of endothelin-1. These effects appear to be mediated at least in part via the actions of urotensin II on a G-protein coupled receptor named GPR-14 or SENR (Ames R S, et al. xe2x80x9cHuman urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14.xe2x80x9d Nature. (1999) 401, 282-6. Mori M, Sugo T, Abe M, Shimomura Y, Kurihara M, Kitada C, Kikuchi K, Shintani Y, Kurokawa T, Onda H, Nishimura 0, Fujino M. xe2x80x9cUrotensin II is the endogenous ligand of a G-protein-coupled orphan receptor, SENR (GPR14)xe2x80x9d Biochem. Biophys. Res. Commun. (1999) 265, 123-9. Liu Q, Pong S S, Zeng Z, et al. xe2x80x9cIdentification of urotensin II as the endogenous ligand for the orphan G-protein-coupled receptor GPR14xe2x80x9d Biochem. Biophys. Res. Commun. (1999) 266, 174-178.) GPR14 is expressed in arterial (but not venous) smooth muscle cells, on atrial and ventricular cardiac myocytes, in pancreas, kidney, and in the brain.
In addition to its vasoconstrictive actions, urotensin II potently affects atrial and ventricular muscle contraction (Russell F D, Molenaar P, and O""Brien D M xe2x80x9cCardiostimulant effects of urotensin-II in human heart in vitroxe2x80x9d. Br J Pharmacol (2001) 132, 5-9).
Urotensin II stimulates cellular proliferation, migration and collagen synthesis in cardiac fibroblasts (Tzandis A, et al., xe2x80x9cUrotensin II stimulates collagen synthesis by cardiac fibroblasts and hypertrophic signaling cardiomyocytes via G(alpha)q- and Ras-dependent pathwaysxe2x80x9d. J. Am. Coll. Cardiol. (2001) 37, 164A.) and in neonatal myocytes (Zou Y, Nagai R, and Yamazaki T, xe2x80x9cUrotensin II induces hypertrophic responses in cultured cardiomyocytes from neonatal ratsxe2x80x9d. FEBS Lett (2001) 508, 57-60). Urotensin II is produced by cancer cell lines and its receptor is also expressed in these cells. (Takahashi K, et al., xe2x80x9cExpression of urotensin II and urotensin II receptor mRNAs in various human tumor cell lines and secretion of urotensin II-like immunoreactivity by SW-13 adrenocortical carcinoma cellsxe2x80x9d. Peptides (2001) 22, 1175-9).
Urotensin II modulates"" glucose-stimulated pancreatic release of insulin (Silvestre R A, et al., xe2x80x9cInhibition of insulin release by urotensin IIxe2x80x94a study on the perfused rat pancreasxe2x80x9d. Horm Metab Res (2001) 33, 379-81).
Elevated circulating levels of urotensin II are detected in humans susceptible to high-altitude pulmonary edema, and in patients awaiting kidney transplantation (Totsune K, et al., xe2x80x9cRole of urotensin II in patients on dialysisxe2x80x9d. Lancet (2001) 358, 810-1).
Urotensin II and its receptor are found in spinal cord and brain tissue, and intracerebroventricular infusion of urotensin II into mice induces behavioral changes (Gartlon J, et al., xe2x80x9cCentral effects of urotensin-II following ICV administration in ratsxe2x80x9d. Psychopharmacology (Berlin) (2001) 155, 426-33).
Substances with the ability to block the actions of urotensin II are accordingly expected to prove useful in the treatment of various diseases. WO-2001/45694 discloses certain sulfonamides as urotensin II receptor antagonists, and their use to treat diseases associated with a urotensin II imbalance. WO-2001/45700 discloses certain pyrrolidines as urotensin II receptor antagonists and their use to treat diseases associated with a urotensin II imbalance. WO-2001/45711 discloses certain pyrrolyl and pyridyl derivatives as urotensin II receptor antagonists and their use to treat diseases associated with a urotensin II imbalance. WO-2002/00606 discloses certain biphenyl compounds useful as urotensin II receptor antagonists, and WO-2002/02530 also discloses certain compounds useful as urotensin II receptor antagonists.
The present invention comprises 1,2,3,4-tetrahydroisoquinoline derivatives which are novel compositions of matter and which are urotensin II receptor antagonists. EP 428434 discloses certain alkylureidopyridines as neurokinin and substance P antagonists. WO-99/21835 discloses certain ureidoquinolines as H+-ATPase and bone resorption inhibitors. WO-01/009088 discloses certain substituted heteroarylureas as inhibitors of the CCR-3 receptor.